TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
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IF 3.8
Yalan Cui,Xuejun Chen,Jingjing Shi,Qian Jin,Ruihua Zhang,Tong Shi,Chen Wang,Liqin Li
Pre-administration of huperzine A (Hup A) was validated to prevent poisoning from exposure to nerve agents (NAs) by reversibly inhibiting acetylcholinesterase (AChE). However, like the currently commonly used reversible inhibitors, Hup A has a short half-life and is unable to produce a long-term preventative effect. To extend the protective time of Hup A against NAs, 42 derivatives with a C N bond were designed based on the structure of Hup A in this study. All designed derivatives showed good binding capability with AChE via molecular docking. Six compounds (H3, H4, H11, H14, H16, and H25) with representative structures were selected for synthesis by Schiff base reaction, and their structures were stable. The modified Ellman's method showed the six compounds concentration-dependently inhibited AChE, and the half maximal inhibitory concentration (IC 50 ) were higher than that of Hup A. Pretreatment of AChE with the derivatives significantly increased the IC 50 of soman . In vivo experiments demonstrated H3, H4, H14, H16, and H25 had longer protective capacities against 1 × LD 95 soman-induced death in mice than Hup A. The 12 h protective index showed that the protective ratios of H3, H4, H14 and H16 were 2.31, 1.85, 2.23 and 1.99 respectively, better than that of Hup A. The extended protection of the derivatives against soman may be explained by their transformation to Hup A in vivo. Furthermore, all six compounds showed lower acute oral toxicity than Hup A. Overall, our study provided an optional strategy to acquire pretreatment agents for NAs with extended action and low toxicity.
研究领域:
药理学
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毒理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL UROLOGY AND NEPHROLOGY
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2020
·Vol. 52
·期 7
·1227-1234
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IF 1.843
Wang Zhenghao,Bai Yunjin,Wang Jiahao,Wang Jia
Objective To investigate the effect of α-lipoic acid (α-LA) in the prevention and treatment of ethylene glycol-induced calcium oxalate deposition in a rat model and preliminary exploration of the mechanism. Methods Sixty male Wistar rats were divided randomly and equally into six groups including two α-LA prevention groups, two α-LA therapeutic groups, one controlled group and one intervention group. Besides controlled group, other group received 1% glycol solution and 2 ml 2% ammonium chloride for 4 weeks as a stone inducer. The prevention groups received 0.1 and 0.2 mg/kg body weight/day/rat α-LA as food supplement during inducing stone and therapeutic groups received 0.1 and 0.2 mg/kg body weight/day/rat α-LA for 4 weeks after 4 weeks stone inducing. Results The volume of urine, the pH and magnesium levels in the preventive and therapeutic groups were higher in a dose-independent manner ( p < 0.05), and urinary calcium was lower ( p < 0.05). Antioxidant stress enzyme activity (glutathione, superoxide dismutase, catalase) in serum and kidney homogenates in the preventive and therapeutic groups underwent significant regeneration ( p < 0.05) and malondialdehyde levels and the production of free radical moieties decreased. Pathological observation demonstrated that there was deformation due to renal tubular expansion in the control group, greater visible inflammatory cell infiltration into the interstitial spaces and partial destruction of the glomerular structures. α-lipoic acid improved the lesions to varying degrees. The extent of crystal deposition was lower in the preventive and therapeutic groups compared with the control group ( p < 0.05). Conclusion The present study indicated that α-LA provides both preventive and therapeutic effects against the deposition of calcium oxalate crystals in rats.
研究领域:
医学
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药理学
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泌尿学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2022
·Vol. 37
·期 3
·e5558
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IF 1.911
Donghua Yu,Jiaqi Fu,Yu Wang,Fang Lu,Pingping Chen,Shumin Liu
This work aims to combine network pharmacology and metabolomics to explore the mechanism of action of dioscin on hyperuricemia (HUA). The preventative impact of dioscin on HUA and its putative mechanism were examined using network pharmacological analysis and metabonomics. Network pharmacology study further pointed out the potential targets of dioscin after a review of the relevant biomarker pathways discovered by metabolomic analysis. Molecular docking was then used to examine how the active chemicals interacted with the target proteins. The therapeutic effect of dioscin on HUA was shown to be mediated by 13 potentially important metabolites as a result of metabonomic research. Most of these metabolites are regulated after dioscin therapy to help patients recover. Based on network pharmacology, we identified 10 central genes, which is partly in agreement with metabolomics data. Using metabolomics and network pharmacology, this study investigated the primary targets and mechanisms of dioscin in the treatment of HUA. It is advantageous that dioscin has been developed as an additional drug for the treatment of HUA.
研究领域:
药理学
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代谢组学
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网络药理学
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分子生物学
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DOI
PubMed
高影响因子
Nature Microbiology
·
2023
·Vol. 8
·期 5
·919-933
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IF 28.3
Han Ji-Xuan,Tao Zhi-Hang,Wang Ji-Lin,Zhang Lu,Yu Chen-Yang,Kang Zi-Ran,Xie Yuanhong,Li Jialu,Lu Shiyuan,Cui Yun,Xu Jia,Zhao Enhao,Wang Ming,Chen Jinxian,Wang Zheng,Liu Qiang,Chen Hui-Min,Su Wenyu,Zou Tian-Hui,Zhou Cheng-Bei,Hong Jie,Chen Haoyan,Xiong Hua,Chen Ying-Xuan,Fang Jing-Yuan
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
研究领域:
肿瘤学
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胃肠病学
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微生物学
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药理学
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DOI
PubMed
高影响因子
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